Transient receptor potential (TRP) channel proteins constitute a large and diverse family of proteins that are expressed in many tissues and cell types. One TRP channel protein of particular interest is the vanilloid receptor 1 (TRPV1 or VR1), a non-selective Ca+2 channel that is the molecular target of vanilloid compounds (e.g., capsaicin and resiniferatoxin). Such vanilloid compounds are known to selectively depolarize nociceptors, specialized primary afferent neurons involved in the signaling pathway that leads to the sensation of pain. TRPV1 is activated by a diverse range of stimuli, including vanilloids, membrane depolarization, heat, stretch, low pH, inflammatory mediators (e.g., lipoxygenase metabolites), and endocannabinoid compounds. Because heightened activity of nociceptors contributes to unwanted pain, inflammatory conditions, thermoregulation, and control of smooth muscle tone and reflexes in mammals, modulation of signaling in this pathway is important in treatment and prophylaxis of various clinical syndromes (Caterina, M. J., Pain 2003, 105(1-2), 5-9; Caterina, M. J. et. al., Annu. Rev. Neurosci. 2001, 24, 487-517; Tominaga, M. et. al., J. Neurobiol. 2004, 61, 3-12; Voets, T. et. al., Nature 2004, 430, 748-754).
Because of TRPV1's connection with the sensory nervous system, TRPV1 agonists and antagonists may be therapeutically useful in the treatment or prophylaxis of disease states, disorders, and conditions mediated by TRPV1 activity, such as: i) pain (e.g., acute, chronic, inflammatory, or neuropathic pain); ii) itch (Kim et al., Neurosci. Lett. 2004, 361, 159) and various inflammatory disorders (Stucky, C. L. et. al., Neuroscience 1998, 84, 1257; Moore, B. A. et. al., Am. J. Physiol. Gastrointest. Liver Physiol. 2002, 282, G1045; Kwak, J. Y. et. al., Neuroscience 1998, 86, 619; Morris, V. H. et. al., Pain 1997, 71, 179; Greiff, L. et. al., Thorax 1995, 50, 225); iii) inner ear disorders (Balaban, C. D. et al., Hear. Res. 2003, 175, 165-70; Zheng, J. et al., J. Neurophys. 2003, 90, 444-55); iv) fever and other disorders or symptoms affected by thermoregulation (Jancso-Gabor et al., J. Physiol. 1970, 206, 495; Swanson et al., J. Med. Chem. 48, 1857; Iida et al., Neurosci. Lett. 2005, 378, 28); v) tracheobronchial and diaphragmatic dysfunction; and vi) gastrointestinal and urinary tract disorders (Lazzeri, M. et al., Eur. Urology 200, 792-798; Apostolidis, A. et. al., Urology 2005, 65, 400-405). Additionally, TRPV1 modulators may be therapeutically useful in the treatment or prophylaxis of anxiety (Marsch, R. et al., J. Neurosci. 2007, 27(4), 832-839); eye-related disorders (such as glaucoma, vision loss, and increased intraocular pressure) (Calkins, D. J. et al., Abstract from ARVO 2006 Annual Meeting, Program #1557, Poster #B93); baldness (e.g., by stimulating hair growth) (Bodo, E. et al., Am. J. Pathol. 2005, 166(4), 985-998); diabetes (including insulin-resistant diabetes or diabetic conditions mediated by insulin sensitivity or secretion) (Razavi, R. et al., Cell 2006, 127(6), 1097-1099; Akiba, Y. et al., Biochem. Biophy. Res. Commun. 2004, 321(1), 219-225).
Acidosis is a well-established feature of cerebral ischaemia. Tissue pH may fall to 6 or lower, sufficient to activate TRPV1 channels expressed in the CNS. TRPV1 antagonists therefore may be useful in the treatment of disorders associated with reduced blood flow to the CNS or CNS hypoxia, such as head trauma, spinal injury, thromboembolic or hemorrhagic stroke, transient ischaemic attacks, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, Alzheimer's disease, and Huntington's Disease.
International Publication No. WO05/014558 (Feb. 17, 2005) describes certain aminopyrimidine inhibitors of voltage-gated sodium and potassium channel. Various bicyclic pyrimidines are disclosed as serotonin receptor modulators in U.S. patent application Ser. No. 11/460,294, filed Jul. 27, 2006. Condensed pyrimidine compounds are disclosed as inhibitors of voltage-gated ion channels in Intl. Publication No. WO 05/014558. Various bicyclic pyrimidines are also disclosed in Intl. Publication No. WO 05/066171 and U.S. Patent Appl. Publ. 2005/0165032 as inhibitors of the TRPV1 channel. However, there remains a need for potent TRPV1 modulators with desirable pharmaceutical properties.